Genetic Variant JAK3:c.*1931delT (chr19-17824811-CA-C) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000215.4(JAK3):c.*1931delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00692 in 194,902 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0066 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0079 ( 1 hom. )

Consequence

JAK3
NM_000215.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.337

Publications

0 publications found

Variant links:

Genes affected

JAK3 (HGNC:6193): (Janus kinase 3) The protein encoded by this gene is a member of the Janus kinase (JAK) family of tyrosine kinases involved in cytokine receptor-mediated intracellular signal transduction. It is predominantly expressed in immune cells and transduces a signal in response to its activation via tyrosine phosphorylation by interleukin receptors. Mutations in this gene are associated with autosomal SCID (severe combined immunodeficiency disease). [provided by RefSeq, Jul 2008]

JAK3 Gene-Disease associations (from GenCC):

T-B+ severe combined immunodeficiency due to JAK3 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

JAK3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP6

Variant 19-17824811-CA-C is Benign according to our data. Variant chr19-17824811-CA-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 328461.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00664 (1012/152304) while in subpopulation NFE AF = 0.0104 (707/68028). AF 95% confidence interval is 0.00976. There are 6 homozygotes in GnomAd4. There are 442 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000215.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAK3	NM_000215.4	MANE Select	c.*1931delT		3_prime_UTR	Exon 24 of 24	NP_000206.2
	JAK3	NM_001440439.1		c.*1931delT		3_prime_UTR	Exon 24 of 24	NP_001427368.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
JAK3	ENST00000458235.7	TSL:5 MANE Select	c.*1931delT	3_prime_UTR	Exon 24 of 24	ENSP00000391676.1	P52333-1
JAK3	ENST00000527031.5	TSL:2	n.2777delT	non_coding_transcript_exon	Exon 14 of 14
JAK3	ENST00000696967.1		n.4483delT	non_coding_transcript_exon	Exon 19 of 19

Frequencies

GnomAD3 genomes

AF:

0.00664

AC:

1011

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00191

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00661

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00348

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0104

Gnomad OTH

AF:

0.0129

GnomAD4 exome

AF:

0.00789

AC:

336

AN:

42598

Hom.:

Cov.:

AF XY:

0.00801

AC XY:

159

AN XY:

19842

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

1698

American (AMR)

AF:

0.00356

AC:

AN:

1124

Ashkenazi Jewish (ASJ)

AF:

0.0106

AC:

AN:

2738

East Asian (EAS)

AF:

0.00

AC:

AN:

7264

South Asian (SAS)

AF:

0.00267

AC:

AN:

374

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00763

AC:

AN:

262

European-Non Finnish (NFE)

AF:

0.0110

AC:

281

AN:

25588

Other (OTH)

AF:

0.00482

AC:

AN:

3524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00664

AC:

1012

AN:

152304

Hom.:

Cov.:

AF XY:

0.00593

AC XY:

442

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00193

AC:

AN:

41550

American (AMR)

AF:

0.00660

AC:

101

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0110

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.00207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00348

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0104

AC:

707

AN:

68028

Other (OTH)

AF:

0.0128

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

101

151

202

252

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00300

Hom.:

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Severe combined immunodeficiency disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.34

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over